Friday, August 30, 2013

Pathophysiology of Depression and Happiness

I'll be on the Creative Live video podcast later today (3pm pacific, 6pm eastern) on the topic of happiness (Dave Asprey invited me to participate, and while he is going into some of the technology he uses to monitor his brain and functioning, I'll be talking about some of the research about happiness and different Eastern and Western perspectives.)

Just going through an amazing review from Neuroscience and Biobehavioral Reviews: Potential roles of zinc in the pathophysiology and treatment of major depressive disorder. I'm going to do an updated zinc post (which is why I pulled the paper), but it does have a terrific and concise review of the biology of depression and, as it happens, happiness. Though this biochemistry will not be part of the talk later today. Suffice it to say (click the diagrams to make them bigger if you like):

So diet provides the amino acid tryptophan, but circumstances can push the metabolism in two directions, toward the neuroprotective, neurogenerative and repair pathway (via serotonin and melatonin) or to the neurotoxic pathway. Stress and inflammation tend to favor the production of kynurenine, which can become quinolinic acid (a potent oxidative agent and neurotoxin) or kynurenic acid (which can go both ways, more on that in a bit).

On the neurotoxic pathway, quinolinic acid triggers the release of glutamate via alpha 7 nicotinic acetylcholine receptors and may also directly stimulate the NMDA receptors. High levels are associated with reduced neuronal growth and repair in the hippocampus of the brain along with markers of neuronal injury. Kynurenic acid, also made from kynurenine, can ameliorate this pathway somewhat by modulating the activity of these alpha 7 nicotinic receptors, but in the wrong amounts kynurenic acid can be neurotoxic as well. In layman's terms you get depressed mood, irritability, suicidal thoughts, memory problems, poor resistance to stress, dysregulated energy metabolism, poor sleep or unrestorative sleep. Poor motivation and reduced concentration. The brain just doesn't function well.


On the bright side you get serotonin and melatonin supporting sleep, appropriate circadian rhythms, appetite and hormonal regulation, and then the effects of reduced excitotoxicity via various receptors and components including 5-HT1A, leading to good memory, good neuronal plasticity (which permits adaptation to new experiences and stimuli), and appropriate levels of brain derived neurotrophic factor and dopamine (some of these are mediated by insulin growth factor 1 by the way) toward neurogenesis and neuroprotection. So here we have good memory, good sleep, regulated energy metabolism, positive outlook, motivation, serenity, and appropriate resiliency to stress.




My apologies for the low tech diagrams, but hey, this is a free blog after all…zinc, by the way, plays a role at almost every level in these pathways. But more on that in a bit!



29 comments:

  1. I gotta include simple hand-drawn diagrams in my next publication! Love the old school look.

    ReplyDelete
  2. @Aaron my college and even early med school days were during times of transparencies rather than powerpoint…I miss those hand-drawn diagrams, and hand-copying them into my notes. It was easier to learn things and teachers had to refine their presentations better than just vomiting out more powerpoint slides….[end rant]

    ReplyDelete
    Replies
    1. Yup, students don't know how bad they have it these days. Especially when they're trying to multitask though they don't realize it interferes with learning. I used to post my powerpoint slides AFTER I lectured on them to force them to take notes during class rather than feeling a false sense of confidence about their learning (called an inflated judgment of learning). But oh how vociferously they complained. So I caved in and now I post the slides before hand. What ever happened to the good old fashioned effort students need to put into learning? [end rant]

      Delete
  3. Will eating more oysters shift our neurochemistry to the left side of your first diagram? I can do that :)

    ReplyDelete
    Replies
    1. You are stealing my zinc punch line, but it does look like some folks (including those with autism, ADHD, and depression) would benefit from a steady source of zinc.

      Delete
    2. Oysters have very high copper which is a zinc antagonist, so it may in fact worsen an imbalance of zinc and copper - it would depend what your zinc and copper ratio is currently like. Red meat would be a better option.

      Delete
  4. Or possibly those people should look at their gut function, gut bacterial imbalances and the excessive inflammation that's causing the zinc problems in the first place?

    ReplyDelete
    Replies
    1. The zinc deficiency question and where the inflammation starts is the holy grail, right?

      Delete
  5. Hmmm... disconcerting - leading to further depression,ug! - that I am very much leaning more and more on the right side of the diagram. I know that I am a very high zinc user (via hypohydrosis and noticing tell-tale white nail spots when not supplementing)and so I have been supplementing with zinc for years now. Still no good. Anything else big like zinc that you might suggest? Always enjoy your articles; thanks for taking the time to write!

    ReplyDelete
    Replies
    1. There are "hair skin and nail" formulas with B vitamins and multiminerals that can be helpful for people. Magnesium, zinc, selenium, copper…but there is a sweet spot for each, of course, not too much, not too little.

      Delete
    2. Ensure you are using zinc picolinate as it's the most bioavailable. If you can access a functional medicine practitioner, ask for some blood tests: plasma zinc, serum copper and see what the ratio is. It should be between 0.75-1:1 (zinc:copper). Plasma zinc is the preferred measure rather than serum zinc. Ensure you have stopped all zinc for 5 days before testing to get an accurate result. You may just need a lot of zinc - I need 150mg/day as I have very high copper levels. Good luck :)

      Delete
  6. Why do melatonin supplements cause depressive symptoms in some?

    ReplyDelete
    Replies
    1. Supplements are way beyond physiologic levels as far as I know. And I get supicious of supplementing hormones because who knows what you are downregulating when you blast the body with the end product? Do you downregulate melatonin by taking it all the time? Or the upstream serotonin? I don't know, and I keep meaning to look into it but haven't.

      I like melatonin for quick jet lag recovery and circadian rhythm support for brief periods, and some of the sleep doctors recommend taking a tiny crumb of the 3mg melatonin tablet, more like 0.5mg at sunset at your destination. I don't really like the idea of chronic, heavy use.

      There are a bunch of studies about a new class of antidepressant that is a melatonin receptor partial agonist, which is interesting, but it is not approved yet and I haven't seen anything recent, so maybe it fizzled out.

      Delete
    2. Hi. Do you mean agomelatine? Yes, it is in use in many countries
      http://www.servier.co.uk/healthcare-professionals/valdoxan/default.asp

      Delete
    3. Hi. Do you mean agomelatine? It is in use in many countries
      http://www.servier.co.uk/healthcare-professionals/valdoxan/default.asp

      Delete
    4. Love the diagrams! Maybe add color next time? They do not have to be so old school :)

      I have also seen websites themes that look like drawn. This will be trendy.

      Delete
    5. OMG... Blogger comments are so difficult. No signal of process.

      Delete
    6. Gabriel: yes, agomelatine (actually forgot the name of it when I was replying to the comment, thanks!). I do have my kids' crayons and markers to make the diagrams look even more homemade…yes, blogger comments are horrible. I keep thinking I should switch to wordpress but everyone is used to the blog being here.

      Delete
  7. I really love this ...thank you. Metametrix Organix/ organic acid test tests for kynurenine and quinolinic acid. If they are elevated the suggestion is to look at magnesium and B6. Zinc seems to play so well with these two that I would think that would be in the suggestions.

    ReplyDelete
  8. I think it is a bit more complicated as quinolic acid is in the de novo NAD(P)+ biogenesis pathway(for ease I will 'incorrectly' call this the B3 biogenesis pathway). It is not known how much a human relies on the B3 bio pathway, though it is likely used to some degree as serotonin producing carcinoid tumors can cause pellagra-like symptoms. This is thought to occur because of the excess tryptophan to serotonin conversion robbing the body of quinolate thus B3.
    Supporting this indirectly is that when tryptophan was first used as an antidepressive it was found effective at much lower doses when niacinamide was added (niacinamide inhibits TDO). I never see this suggestion anymore. So niacinamide supplementation is something that I think might need to be considered in certain circumstances, especially when supplementing tryp.

    ReplyDelete
    Replies
    1. Yes, I left out all of the detail of QA, plan to go into it later in the more zinc-focused post. Maybe. Maybe it will take a 3rd post if there is interest. It is such nitty-gritty and requires a pretty advanced understanding of receptors, kinetics, etc.

      Delete
    2. I took niacinamide and had cold sores within 24 hours. Won't be trying that again.

      Delete
    3. I could find no link between niacinamide (nicotinamide) intake and Herpes (HSV-1) reactivation in Pubmed. As this vitamin has been used for years and HSV-1 is common this means that your results were probably coincidental. (I also couldn't find any anecdotes through Google.) Hopefully your experience does not scare people with HSV-1 away from trying niacinamide if they are depressed(especially if they have low NAD+ levels or need to shift their tryptophan metabolism towards the serotonin pathway)

      Delete
  9. What is the daily recommendation for zinc for a male?

    ReplyDelete
    Replies
    1. See: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3715721/pdf/fnagi-05-00033.pdf and also:PMID:
      23602205, Effects of zinc supplementation on efficacy of antidepressant therapy, inflammatory cytokines, and brain-derived neurotrophic factor in patients with major depression. 25 mg per day of elemental zinc were used.

      Delete
  10. I was really looking forward to seeing on Creative Live, but then I feel asleep and missed most of it. When I woke up Dave was making a comment about glasses, something like "by the way we didn't coordinate at all". Where you talking about blue blockers and melatonin production, or where you talking about different types of glasses?

    ReplyDelete
    Replies
    1. Blue light blocking.
      You can listen to the interview here
      https://soundcloud.com/nootropicos/dr-emily-deans-interview-with

      Delete
  11. A NYtimes piece by Nobel Laureate Erik Kandel that may be an interesting read for followers of this blog:

    http://www.nytimes.com/2013/09/08/opinion/sunday/the-new-science-of-mind.html?pagewanted=2&_r=0&ref=general&src=me

    ReplyDelete
  12. Thanks for your most informative postings. Just wondering, if a person does have high quinolinic acid, what can be done about it?

    ReplyDelete